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Pain relief without the numbness

Oct. 3, 2007
Courtesy Harvard Medical School
and World Science staff

An­y­one who has received a stiff dose of pain­kill­er knows that full pain re­lief is al­most un­im­ag­in­able with­out an ac­com­pa­ny­ing numb­ness, if not un­con­scious­ness. 

But that’s only be­cause we don’t know a bet­ter way, re­search­ers say. In fact, the nerve cells that sense pain­ful stim­u­li are dis­tinct from those that pick up oth­er sens­ati­ons. So it should be pos­si­ble to knock out the first type and not the oth­ers, and thus wipe out the pain alone. Cur­rent drugs in­stead zap nerve cells in­dis­cri­mi­nately, ex­plain­ing their dras­tic side ef­fects.
In a new study with rats, sci­en­tists claim to have fi­nally fig­ured out how to knock out the pain-sens­ing cells only, potentially re­vo­lu­tion­iz­ing pain treat­ment. 

The catch: as it stands, the new tech­nique involves an init­ial injection of hot pep­per spice—a brief burst of pain as the price of re­prieve from later suf­fer­ing. The re­search­ers hope to later find a way to avoid this un­pleas­ant­ness.

“Even­tually this meth­od could com­pletely trans­form sur­gi­cal and post-sur­gi­cal an­al­ge­sia, al­low­ing pa­tients to re­main fully alert with­out ex­pe­ri­encing pain or paral­y­sis,” said Clif­ford Woolf of Mas­sa­chu­setts Gen­er­al Hos­pi­tal in Bos­ton. He is the sen­ior au­thor of a pa­per on the find­ings to ap­pear in the Oct. 4 is­sue of the re­search jour­nal Na­ture. Woolf said the find­ings raise the odd pos­si­bi­lity that you could, for example, feel a pin­prick as a norm­al sen­sa­tion, but with­out dis­com­fort.

De­spite in­tense re­search, sur­gi­cal pain man­age­ment has changed lit­tle since the first demon­s­tra­tion of gen­er­al an­es­the­sia at Mas­sa­chu­setts Gen­er­al in 1846, us­ing ether, Woolf and col­leagues said. The new stu­dy, con­duct­ed with sci­ent­ists at Har­vard Med­i­cal School in Bos­ton, builds on re­search done since the 1970s. This has ex­am­ined how elec­tri­cal sig­nal­ing among nerve cells de­pends on pro­tein mo­le­cules called ion chan­nels. The chan­nels form open­ings in the mem­branes, or skin-like pro­tec­tive cov­er­ing, of neu­rons, or nerve cells.

One such chan­nel, called TR­PV1, ex­ists only in pain-sensing neu­rons, Woolf and col­leagues said. Mo­le­cules can en­ter and ex­it the cell through the chan­nel. But a mo­lec­u­lar “gate” typ­ic­ally blocks the open­ing. The gate opens in re­sponse to heat or to the spicy in­gre­di­ent of chili-pep­pers, cap­sa­i­cin. 

The in­ves­ti­ga­tors in­jected rats with cap­sa­i­cin and a com­pound called QX-314, a nor­mally in­ac­tive de­riv­a­tive of a lo­cal an­es­thet­ic, li­do­caine. Be­cause the chan­nels were open, the chem­i­cal was able to en­ter the cells and shut them down, the re­search­ers found. But oth­er types of nerve cells were un­af­fect­ed be­cause they don’t have TR­PV1 chan­nels.

“We’re op­ti­mis­tic that this meth­od will even­tu­ally be ap­plied to hu­mans and change our ex­pe­ri­ence dur­ing pro­ce­dures rang­ing from knee sur­gery to tooth extracti­ons,” said Woolf. The treated rats seemed im­mune to pain, such as un­comforta­ble heat and pricks; yet they con­tin­ued to move nor­mally and re­spond to oth­er stim­u­li, the in­ves­ti­ga­tors found.

But there are sev­er­al hur­dles to over­come be­fore the meth­od can be ap­plied to hu­mans, they said: it’s un­clear how to open the chan­nel with­out pro­duc­ing a tem­po­rary burn­ing pain, and the treat­men­t’s ef­fects aren’t long enough yet for clin­i­cal use. But it should be pos­si­ble to solve these prob­lems, Woolf claimed. “The pos­si­bil­i­ties seem end­less,” he added. “I could even im­ag­ine us­ing this meth­od to treat itch, as itch-sensitive neu­rons fall in­to the same group as pain-sensing ones.”

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Anyone who has gotten a stiff dose of painkiller knows it’s almost impossible to imagine full pain relief without an accompanying numbness, if not unconsciousness. But if these effects seem inescapably linked, that’s only because we don’t know a better way, researchers say. In fact, the nerve cells that sense painful stimuli are distinct from those that pick up other sensations. So it should be possible to knock out the first type of cell and not the others, wiping out the pain only. Current drugs can’t do that: they disable all types of nerve cells, explaining their wide-ranging side effects. In a new study with rats, scientists claim to have finally figured out how to knock out the pain-sensing cells only. “Eventually this method could completely transform surgical and post-surgical analgesia, allowing patients to remain fully alert without experiencing pain or paralysis,” said Clifford Woolf of Massachusetts General Hospital, senior author of a paper on the findings to appear in the Oct. 4 issue of the research journal Nature. Despite intense research, surgical pain management has changed little since the first demonstration of general anesthesia at Massachusetts General using ether in 1846, Woolf and colleagues said. The new study, they added, builds on research done since the 1970’s on how electrical signaling among nerve cells depends on protein molecules called ion channels. Ion channels form openings in the membranes, or skin-like protective covering, of neurons. One such channel, called TRPV1, exists only in pain-sensing neurons, Woolf and colleagues said. Molecules can enter and exit the cell through the channel. But a molecular “gate” typically blocks the opening. The gate opens in response to heat or to the spicy ingredient of chili-peppers, capsaicin. The investigators injected rats with capsaicin—the ingredient that gives hot peppers their spice—and a compound called QX-314, a normally inactive derivative of a local anesthetic, lidocaine. Because the channels were open, the chemical was able to enter the cells and shut them down, the researchers found. But other types of nerve cells were unaffected because they don’t have TRPV1 channels. “We’re optimistic that this method will eventually be applied to humans and change our experience during procedures ranging from knee surgery to tooth extractions,” said Woolf. The treated rats seemed immune to pain, such as uncomfortable heat and pricks; yet they continued to move normally and respond to other stimuli, the investigators found. But there are several hurdles to overcome before the method can be applied to humans, they said: it’s unclear how to open the channel without producing a temporary burning pain, and the treatment’s effects aren’t long enough yet for clinical use. But it should be possible to solve these problems, Woolf said. “The possibilities seem endless,” he added. “I could even imagine using this method to treat itch, as itch-sensitive neurons fall into the same group as pain-sensing ones.”